Inflammatory bowel disease (IBD) is the general name for diseases that cause inflammation in the small intestine and colon. Ulcerative colitis is the most common inflammatory bowel disease and it affects various portions of the gastrointestinal (GI) tract, particularly the lower GI tract, and more particularly the colon and/or rectum. A second IBD is Crohn's disease, which predominates in the small intestine (ileum) and the large intestine (colon).
Ulcerative colitis can be difficult to diagnose in that its symptoms are similar to other intestinal disorders and to Crohn's disease. Crohn's disease differs from ulcerative colitis because it causes deeper inflammation into the intestinal wall. Also, Crohn's disease usually occurs in the small intestine, although it can also occur in the mouth, esophagus, stomach, duodenum, large intestine, appendix, and anus.
Ulcerative colitis may occur in people of any age, but most often it starts between ages 15 and 30, or less frequently between ages 50 and 70. Children and adolescents sometimes develop this disease. Ulcerative colitis affects men and women equally and appears to run in some families.
It is also important to consider that about 5 percent of people with ulcerative colitis develop colon cancer. The risk of cancer increases with the duration and the extent of involvement of the colon. For example, if only the lower colon and rectum are involved, the risk of cancer is no higher than normal. However, if the entire colon is involved, the risk of cancer may be as much as 32 times the normal rate. Thus, it is possible that drugs useful in the treatment of IBD may also be useful in the prevention of colon cancer.
The pathogenesis of IBD likely involves multifactorial interactions among genetic factors, immunological factors and environmental triggers. Recent evidence suggests that a pathologic activation of the mucosal immune system in response to antigens is a key factor in the pathogenesis of IBD.
The presentation of antigen in the inflammatory process is closely followed by generation of cytokines, small glycoprotein peptide molecules, which provide signals for the communication among different cell populations determining the direction of subsequent immune and inflammatory response. Pro-inflammatory cytokines include interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor-alpha (TNF-α). Macrophages are the major source of cytokines, with epithelial cells also being able to produce a number of these peptide factors.
T helper (Th) cells are a further important source of cytokines. Th1 cells, which are associated with a cell-mediated immune response, produce IL-2, interferon gamma (IFN-γ) and TNF-α. A key transcription factor involved in the regulation of inflammation, NFkB, which is specifically implicated in the pathogenesis of IBD, regulates the amount of cytokines produced by the Th1 cells (see Neurath et al. (1996) Nature Med. 2: 998-1004). Th2 cells enhance antibody synthesis by B cells and produce IL-4, IL-5, IL-6, and IL-10.
Chemokines are also thought to contribute to the pathogenesis of colitis. Chemokines are pro-inflammatory proteins that participate in immune and inflammatory responses through the chemoattraction and activation of leukocytes. For example, RANTES is a C—C chemokine that promotes the recruitment and activation of inflammatory cells such as monocytes, lymphocytes, mast cells and eosinophils. RANTES has recently been shown to be elevated during the chronic phase of colitis (see Ajuebor et al. (2001) J. Immunol. 166: 552-558).
There is increasing evidence to show that nitric oxide, which is a free radical endogenous messenger molecule, exerts many actions in the GI tract. Recently it has been shown agents that agents that release nitric oxide (NO) in small amounts over a prolonged period of time can greatly reduce inflammation and can accelerate healing in experimental colitis. Further, an NO-releasing derivative of mesalamine has been shown to be more effective than mesalamine in reducing the severity of colitis, in particular, damage and granulocyte infiltration (see Wallace, J. L. et al. (1999) Gastroenterology 117: 557-66).
Nitric oxide has also been shown to be a potent mediator that induces relaxation in vascular smooth muscle and, in this manner, regulates the basal tone of the arterioles, performing an important role in the control of blood flow to the intestinal mucosa. Studies of experimental models using ischemia, hypoxia, toxins or platelet activating factor to induce intestinal damage have shown that inhibiting nitric oxide synthesis is associated with increased tissue damage whereas if it is supplied exogenously the effect is attenuated (Payne, D. and Kubes, P. (1993) Am. J Physiol. 265: G189-95; Caplan, M. S. et al. (1993) Gastroenterol. 28: 149-54; Kubes, P. (1993) Am. J Physiol. 264: G143-9).
Arginine is an amino acid that is a source of nitrogen for nitric oxide production. It has previously been shown that a continuous infusion of arginine attenuated intestinal injury in an experimental model and also significantly reduced intestinal tissue damage in mice subjected to hypoxia followed by re-oxygenation (Di Lorenzo, M. et al. (1995) Pediatr. Surg. 30: 235-40; Akisu, M. et al. (2002) Biol. Neonate 81:260-5).
Treatment for ulcerative colitis depends on the seriousness of the illness. Most people are treated with medication. In severe cases, a patient may need surgery to remove the diseased colon.
Irritable bowel syndrome (IBS) is a common but poorly understood disorder that causes a variety of bowel symptoms including abdominal pain, diarrhea and/or constipation, bloating, gassiness and cramping. While these symptoms may be caused by a number of different bowel diseases, IBS is usually diagnosed only after exclusion of a more serious problem. There is increasing evidence suggesting the role of inflammation in the pathogenesis of IBS.
The goal of therapy is to induce and maintain remission, and to improve the quality of life for people with IBD/IBS. Several types of drugs are available.
Aminosalicylates, which are drugs that contain 5-aminosalicylic acid (5-ASA or mesalamine) or 4-aminosalicylic acid (4-ASA), help to control the inflammation. However, both mesalamine and 4-ASA may be absorbed as it passes through the GI tract and may adversely affect the amount of mesalamine that reaches the lower GI tract, particularly the colon and rectum. Thus, various mesalamine formulations have been introduced in an attempt to protect mesalamine as it passes through the gut and upper GI tract.
In addition, several pro-drugs of mesalamine have been introduced which can aid in colon-specific delivery of mesalamine. These pro-drugs are generally less readily absorbed in the gut and upper GI tract and thus can more easily reach the colon. An example of one such drug is sulfasalazine, which is a combination of sulfapyridine and 5-ASA linked via an azo bond and is employed to induce and maintain remission. Sulfasalazine is metabolized in the body to form 5-ASA and sulfapyridine. The sulfapyridine component carries the anti-inflammatory 5-ASA to the intestine.
However, sulfapyridine may lead to side effects, such as nausea, vomiting, heartburn, diarrhea, and headache. These adverse side effects are usually attributed to the activity of sulfapyridine in the GI tract, as well as that absorbed into the system.
There is a need for a drug with improved activity over sulfazalazine without similar side effects and in the possibility of achieving such improvement with 4- or 5-ASA as the starting point.